IFN-alpha and IL-12 activate IFN regulatory factor 1 (IRF-1), IRF-4, and IRF-8 gene expression in human NK and T cells

Cytokine. 2003 Nov 7;24(3):81-90. doi: 10.1016/j.cyto.2003.07.001.

Abstract

IFN-alpha and IL-12 are macrophage-derived cytokines that enhance innate and Th1 immune responses. However, there is little information regarding IFN-alpha and IL-12 target genes that would be involved in mediating the immunostimulatory effects of these cytokines. The interferon regulatory factor (IRF) family of transcription factors is known to be involved in controlling lymphocyte differentiation and functions. In this work we have studied the effect of IFN-alpha and IL-12 on the expression of IRF transcription factors in human NK and T cells. Both IFN-alpha and IL-12 strongly up-regulated IRF-1, IRF-4, and IRF-8 mRNA and protein expression. The binding of IRF-4 and IRF-8 to the lambdaB gene enhancer sequence was also increased following IFN-alpha- and IL-12-treatment of NK and T cells. A GAS element from the promoter region of the IRF-4 gene was identified. Following stimulation of cells with IFN-alpha or IL-12, Stat4 was found to bind to this IRF-4 GAS element, as detected by EMSA and DNA affinity binding, implying that the IRF-4 gene is directly activated by both cytokines. Our results suggest that IFN-alpha and IL-12 may enhance innate and Th1 immune responses by inducing IRF-1, IRF-4, and IRF-8 gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Polarity
  • Cells, Cultured
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Humans
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factors
  • Interferon-alpha / metabolism
  • Interferon-alpha / pharmacology*
  • Interleukin-12 / metabolism
  • Interleukin-12 / pharmacology*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / physiology
  • Phosphoproteins / drug effects
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins / drug effects
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • STAT4 Transcription Factor
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / drug effects
  • Transcription Factors / genetics*

Substances

  • DNA-Binding Proteins
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factors
  • Interferon-alpha
  • Phosphoproteins
  • Repressor Proteins
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • Trans-Activators
  • Transcription Factors
  • interferon regulatory factor-4
  • interferon regulatory factor-8
  • Interleukin-12